α, β-unsaturated ketones and ketoxime derivatives

ABSTRACT

The present invention provides an α, β-unsaturated ketone and ketoxime derivative represented by the formula ##STR1## wherein Y is oxygen atom or hydroxyimino group, Z is cyano or alkoxycarbonyl group, R 1  and R 2  are the same or different and are each hydrogen atom or lower alkoxyl group. 
     The α, β-unsaturated ketones and ketoxime derivatives of the invention are useful as an intermediate for preparing a (3,4-diarylisoxazol-5-yl)acetic acid derivatives which is useful as an anti-inflammatory agent, analgesic and antipyretic.

TECHNICAL FIELD

The present invention relates to α,β-unsaturated ketone and ketoximederivatives which are novel compounds. The present compounds are usefulas intermediates for preparing (3,4-diarylisoxazol-5-yl)acetic acidderivatives which are represented by the formula ##STR2## wherein R¹ andR² are the same or different and are each a hydrogen atom or loweralkoxyl, and which are useful as anti-inflammatory agents, analgesicsand antipyretics.

BACKGROUND ART

JF-A-59764/1981 discloses (3,4-diarylisoxazol-5-yl)acetic acidderivatives as a compound having anti-inflammatory, analgesic andantipyretic activities. The processes thereof are known in (1) the abovepublication and (2) JP-A-75471/1985.

JP-A-59764/1981 ##STR3## wherein R¹ and R² are as defined above.

The above contemplated compound is obtained by reacting3,4-diaryl-5-methylisoxazole with n-butyl lithium in tetrahydrofuranwhile cooling by use of dry ice-acetone mixture, pouring the reactionmixture into pulverized dry ice, and then treating the mixture withacid.

JP-A-75471/1985 ##STR4## wherein X is halogen atom, R¹ and R² are asdefined above. This process comprises reacting3,4-diaryl-5-methylisoxazole with a halogenating agent and then with acyanogenation agent to obtain 3,4-diaryl-5-cyanomethylisoxazole, andsubjecting the same to solvolysis.

The present inventors have investigated an industrial process forpreparing (3,4-diarylisoxazol-5-yl)acetic acid derivatives and found themethods disclosed in (1) and (2) have various problems. In the method(1), the reagent, n-butyl lithium, is liable to ignite and causesproblems in fire and safety when used in a large quantity. Further, thismethod comprises problems in process efficiency including operationefficiency, because dry ice having high hygroscopicity is used in thereaction which requires anhydrous reaction condition and low temperature-70°C. The method (2) is more complicate than the method (1), and is nota preferable industrial process in view of safety due to the use ofcyano compound.

An object of the present invention is to provide novel α,β-unsaturatedketone and ketoxime derivatives useful as intermediates for preparingthe compound (A) by a simple process which uses no dangerous reagent andis excellent in safety and operation efficiency.

DISCLOSURE OF THE INVENTION

The present invention provides an α,β-unsaturated ketone and ketoximederivative represented by the formula ##STR5## wherein Y is oxygen atomor hydroxyimino group, Z is cyano or alkoxycarbonyl group, R¹ and R² arethe same or different and are each hydrogen atom or lower alkoxyl group.

In the present invention, examples of alkoxycarbonyl groups representedby Z are straight-chain or branched-chain alkoxycarbonyl groups having 2to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, secbutoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl and hexyloxycarbonyl. Examples of lower alkoxyl groupsrepresented by R¹ and R² are straight-chain or branched-chain loweralkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy. tert-butoxy,pentyloxy and hexyloxy. The present α,β-unsaturated ketone and ketoximederivatives are useful as intermediates for preparing(3,4-diarylisoxazol-5-yl)acetic acid derivatives which are useful asanti-inflammatory agents, analgesics and antipyretics and which arerepresented by the formula ##STR6## wherein R¹ and R² are the same ordifferent and are each a hydrogen atom or lower alkoxyl group.

The compound (I) in the present invention is prepared, for example, inaccordance with the following reaction scheme. ##STR7## wherein Z, R¹and R² are as defined above, and R³ is lower alkyl group.

Examples of lower alkyl groups represented by R³ in the above scheme arestraight-chain or branched-chain alkyl groups having 1 to 6 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl and hexyl.

More specifically, the steps represented by the above reaction schemeare performed in the following manner.

Step A

A deoxybenzoin derivative represented by the formula (II) is reactedwith an alkoxyacrylonitrile or alkoxyacrylic acid derivative representedby the formula (III) in a suitable solvent in the presence of a base toobtain a desired compound of the formula (I a). The solvent is notlimited specifically insofar as it does not participate in the reaction.Examples of useful solvents are various organic solvents includingmethanol, ethanol, tert-butanol and like alcohols, tetrahydrofuran,dioxane and like ethers, benzene, toluene, xylene and like aromatichydrocarbons, carbon tetrachloride, dichloroethane and like hydrocarbonhalides, pyridine, dimethyliormamide. etc. These solvents can be usedsingly or in admixture. Examples of useful bases are sodium hydroxide,sodium hydride, sodium amide, sodium methoxide, potassium tert-butoxide,sodium tert-butoxide, butyl )ithium and like alkali bases,triethylamine, diethylaminopyridine and like organic bases, etc. For thereaction, it is desirable to use 1 to 3 moles of the compound of theformula (III) per mole of the compound of the formula (II), and 0.1 to 3moles of the base per mole of the compound of the formula (II). Thereaction is conducted at a temperature of up to 200°C., preferably from0° C. approximately to the boiling point of the solvent. The reactionusually takes about 0.5 to about 20 hours for completion.

Step B

The compound represented by the formula (I a) and obtained by step A isreacted with hydroxylamine or a salt thereof in a suitable solvent tothereby obtain a desired compound represented by the formula (I b). Thesalt of hydroxylamine to be used for the reaction is not limitedspecifically and is, for example, the commercially availablehydrochloric acid salt, sulfuric acid salt or the like. The solvent isnot limited specifically insofar as it does not participate in thereaction. Examples of useful solvents are various organic solventsincluding methanol, ethanol, isopropanol and like alcohols,tetrahydrofuran, dioxane and like ethers, dimethylformamide, etc. Thesesolvents can be used singly or in admixture, or in the form of a mixturethereof with water. For the reaction, it is desirable to use 1 to 10moles of hydroxylamine or a salt thereof per mole of the compound of theformula (I a). The reaction is conducted at a temperature of 0° to 200°C., preferably from 40° C. approximately to the boiling point of thesolvent. The completion of the reaction usually takes about 1 to about30 hours. Further, it is possible as required to add an acid or base tothe reaction system, or to conduct the reaction in a solvent mixturewith a buffer solution, etc.

The compound of the invention thus obtained can be isolated and purifiedby usual known methods, for example, by distillation, recrystallizationor silica gel column chromatography.

In the present invention, α,β-unsaturated ketone and ketoximederivatives of the formula (I) include isomers due to the double bond,and both isomers are included in the present invention.

The ketoxime compound represented by the formula (I b) and prepared bythe above process is subjected, as isolated or as it is withoutisolation, to cyclization with use of a halogenating agent in a suitablesolvent to obtain (3,4-diarylisoxazol-5-yl)acetate derivative or(3,4-diarylisoxazol-5-yl)acetonitrile derivative, and further thederivative is subjected to solvolysis or to hydrolysis in the presenceof an acid or base, whereby a (3,4-diarylisoxazol-5-yl)acetic acidderivative represented by the formula (A) and having anti-inflammatoryand analgesic activities can be derived from the compound of theinvention. The halogenating agent is not limited specifically and is,for example, chlorine, bromine, iodine, N-chlorosuccinimide,N-bromosuccinimide, or the like. The solvent is not limited specificallyinsofar as it does not participate in the reaction. Examples of usefulsolvents are dichloromethane, chloroform, carbon tetrachloride and likehydrocarbon halides, benzene, toluene and like aromatic hydrocarbons,methanol, ethanol and like alcohols, diethyl ether, tetrahydrofuran andlike ethers, acetone, hexane, etc. In the above cyclization, it ispreferable to use 1 to 3 moles of the halogenating agent per mole of theketoxime compound of the formula (I b). The reaction is conducted at atemperature of -70° to 150° C., preferably from -20° C. approximately tothe boiling point of the solvent. The solvolysis or hydrolysis can beconducted by solvolysis process disclosed in JP-A-75471/1985 or by thehydrolysis process generally employed in the art concerned. Generallyused as the acid is an inorganic acid such as hydrochloric acid,sulfuric acid or nitric acid, or as the base is an inorganic base suchas sodium hydroxide, potassium hydroxide or sodium carbonate. Thelater-mentioned Reference Example shows the detail of synthesis of(3,4-diarylisoxazol-5-yl)acetic acid derivative from the compound of thepresent invention.

Best mode of carrying out the invention

The present invention will be described below in detail with referenceto examples and reference examples.

EXAMPLE 1 Preparation of methyl4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate

To 430 ml of tert-butanol were added 128 g of deoxyanisoin, 67.3 g ofpotassium tert-butoxide and 116 g of methyl 3-methoxyacrylate, and themixture was stirred at 70° C. for 3 hours. After the completion ofreaction, the reaction mixture was allowed to stand at room temperaturewith addition of n-hexane. The product separating out was filtered offand the residue was dried at a reduced pressure, giving 175 g (yield92%) of potassium salt of the above-identified compound as a yellowsolid.

IR absorption spectrum (KBr): νmax(cm⁻¹) 1734, 1664, 1604.

NMR spectrum (pyridine-d₅) δ(ppm) 3.58(3 H, s), 3.60(3 H, s), 3.66(3 H,s), 5.65(1 H, d), 6.83(2 H, d), 6.94(2 H, d), 7.64(2 H, d), 7.81(2 H,d), 9.01(1 H, d).

The above potassium salt was dissolved with 1000 ml of ethyl acetate and300 ml of 3N sulfuric acid. The organic layer was collected, washed with3N sulfuric acid and a saturated aqueous solution of sodium chloride,and dried over anhydrous sodium sulfate. The organic layer wasconcentrated at a reduced pressure, giving 153 g (yield 90%) of theabove-identified compound as an oily product.

An NMR spectrum revealed that the compound was a mixture of isomers(about 6:4) due to a double bond. The mixture was recrystallized fromhexane-ethyl acetate as required, whereby one of the isomers wasisolated in the form of white crystals.

Melting point 101°˜103° C.

IR absorption spectrum (KBr): νmax(cm⁻¹) 1732, 1640, 1600.

NMR spectrum (CDCl₃) δ(ppm): 3.31(2 H, d), 3.72(3 H, s), 3.80(3 H, s),3.85(3 H, s), 6.37(1 H, t), 6.90(4 H, d), 7.23(2 H, d), 7.89(2 H, d).

The mother liquor further gave the other isomer of the compound in theform of an oily product.

IR absorption spectrum (KBr): νmax(cm⁻¹) 1732, 1662, 1596.

NMR spectrum (CDCl₃) δ(ppm) 3.15(2 H, d), 3.65(3 H, s), 3.77(3 H, s),3.83(3 H, s), 6.30(1 H, t), 6.6˜7.1(4 H, m), 7.30(2 H, d), 7.92(2 H, d).

EXAMPLE 2 Preparation of 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenenitrile

The identified compound was obtained as an oily product by conductingthe same reaction as in Example 1 with the exception of using3-methoxyacrylonitrile instead methyl of 3-methoxyacrylate.

IR absorption spectrum (NaCl): νmax(cm⁻¹) 2250, 1660, 1606.

NMR spectrum (CDCl₃) δ(ppm): 3.17(2 H, d), 3.78(3 H, s), 3.85(3 H, s),6.03(3 H, t), 6.7˜7.0(4 H, m), 7.27(2 H, d), 7.90(2 H, d).

EXAMPLE 3 Preparation of methyl5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate

A 24.5 g quantity of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoateobtained in Example 1 and 51.5 g of hydroxylamine hydrochloride wasrefluxed with heating in a mixture of 650 ml of methanol and 72 ml ofwater for 23 hours. With the progress of reaction at this time, 0.9equivalent weight of sodium hydrogentarbonate was added in dividedportions to the reaction system. On completion of the reaction, themethanol was distilled off at a reduced pressure. The residue wasdissolved with water and ethyl acetate, and the organic layer wascollected, washed with a saturated aqueous solution of sodium chlorideand dried over anhydrous magnesium suliate. The organic layer wasconcentrated at a reduced pressure, and the residue was subjected tosilica gel column chromatography (eluants: ethyl acetate-n-hexane) forseparation and purification, affording 23 g (yield 90%) of theabove-identified compound as an oily product.

IR absorption spectrum (NaCl) νmax(cm⁻¹) 1732, 1608.

NMR spectrum (CDCl₃) δ(ppm): 3.09˜3.20(2 H, m), 3.65(3 H, s), 3.76(3 H,s), 3.77(3 H, s), 6.48(1 H, t), 6.81(4 H, d), 7.35(2 H, d), 7.58(4 H,d), 8.72(1 H, bs).

EXAMPLE 4 Preparation of5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenenitrile

The identified compound was prepared as an oily product by conductingthe same reaction with hydroxylamine hydrochloride as in Example 3 withthe exception of using 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenenitrilein place of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate.

IR spectrum (NaCl):

νmax(cm⁻¹) 2252, 1596.

NMR spectrum (CDCl₃) δ(ppm): 3.12, 3.15(2 H, dd), 3.77(3 H, s), 3.78(3H, s), 6.18(1 H, t), 6.84(4 H, d), 7.32(2 H, d), 7.55(2 H, d), 8.46(1 H,bs).

Reference Example 1 Preparation of methyl(3,4-bis(4-methoxyphenyl)-isoxazol-5-yl]acetate

In 50 g of benzene was dissolved 3.05 g of methyl5-hydroxyimino-4,5-bis(4-methoxyphenyl-3-pentenoate obtained in Example3. Thereto was added gradually 3.91 g of N-bromosuccinimide at roomtemperature and the mixture was stirred at the same temperature for 2hours. After completion of the reaction, ethyl acetate was added to thereaction mixture for dilution, and the organic layer was washed with anaqueous solution of potassium carbonate and then with a saturatedaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The organic layer was concentrated at a reduced pressure, andthe residue was subjected to silica gel column chromatography (eluants:ethyl acetate-n-hexane) and crystallized from ether, giving theabove-identified compound.

Melting point 67°˜68° C.

IR absorption spectrum (KBr) νmax(cm⁻¹) 1730.

NMR spectrum (CDCl₃) δ(ppm): 3.73(3 H, s), 3.77(2 H, s), 3.79(3 H, s),3.82(3 H, s), 6.83(2 H, d), 6.90(2 H, d), 7.15(2 H, d), 7.40(2 H, d).

Reference Example 2 Preparation of[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetic acid

To 15 ml of 2% aqueous solution of sodium hydroxide was added 1.77 g ofmethyl [3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetate obtained inReference Example 1 and the mixture was stirred at 40° C. over night.After completion of the reaction, the reaction mixture was washed withether twice, and thereto was added 5 ml of 10% HCl while cooling withice. The mixture was extracted with ethyl acetate, and the organic layerwas washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. The organic layer wasconcentrated at a reduced pressure, giving the above-identified compoundas white solid.

Melting point 147°˜148° C.

IR absorption spectrum (KBr): νmax(cm⁻¹) 1728.

NMR spectrum (CDCl₃) δ(ppm): 3.79(3 H, s), 3.81(2 H, s), 3.83(2 H, s),6.82(2 H, d), 6.92(2 H, d), 7.15(2 H, d), 7.40(2 H, d), 10.10(1 H, bs).

Industrial applicability

The α,β-unsaturated ketones and ketoxime derivatives of the inventionare useful as an intermediate for preparing a(3,4-diarylisoxazol-5-yl)acetic acid derivative which is useful as ananti-inflammatory agent, analgesic and antipyretic and which isrepresented by the formula ##STR8## wherein R¹ and R² are the same ordifferent and are each a hydrogen atom or lower alkoxyl group.

We claim:
 1. An α,β-unsaturated ketone and ketoxime derivativerepresented by the formula ##STR9## wherein Y is an oxygen atom or ahydroxyimino group, Z is a cyano or an alkoxycarbonyl group, and R¹ andR² are the same or different and are each a hydrogen atom or loweralkoxyl group; provided, however that when Z is an alkoxycarbonyl group,then R¹ and R² are the same or different and are each a lower alkoxylgroup.
 2. An α,β-unsaturated ketone and ketoxime derivative representedby the formula ##STR10## wherein Y is an oxygen atom or a hydroxyiminogroup, Z is a cyano or an alkoxycarbonyl group, and R¹ and R² are thesame or different and are each a lower alkoxyl group.
 3. Anα,β-unsaturated ketone and ketoxime derivative represented by theformula ##STR11## wherein Y is an oxygen atom or a hydroxyimino group, Zis a cyano group and R¹ and R² are the same or different and are each ahydrogen atom or lower alkoxyl group.